The Passerini reaction, the three-component reaction between a carboxylic acid, a carbonyl compound such as an aldehyde or a ketone, and an isocyanide, offers direct access to α-acyloxy carboxamide derivatives (Scheme 1, eq 1). This is the first isocyanide based multicomponent reaction playing a central role in combinatorial chemistry, and is widely utilized for the synthesis of various drug-like molecules, and in the total synthesis of biologically active natural products. Intriguingly, the Passerini reaction employing ketones is generally slower and in some cases, the reactions carried out with bulky carbonyl substrate and the bulky isocyanide fail to afford the desired product. However, the use of high pressure is one way to increase the efficiency of Passerini reactions involving bulky reactants.

In the context of the Passerini reactions of sterically congested carbonyl compounds, it was envisaged that the multicomponent reaction involving isatin derivatives, isocyanides and carboxylic acids could provide a simple and straightforward access to oxindole derivatives (eq 2). This will be interesting because oxindoles having a quaternary benzylic centre represent a common structural motif in many natural products and biologically active compounds. Among them, the oxindoles with heteroatom at the benzylic position are useful class of compounds including the bioactive natural products (R)-convolutamydine A, maremycin B and the potent growth hormone secretion promoter SM-130686 (FIG. 1).

FIG. 1: Selected biologically active oxindoles having a quaternary benzylic centre having OH group.
Esmaeili et al. in “A novel and efficient synthesis of 3,3-disubstituted indol-2-ones via Passerini three-component reactions in the presence of 4 Å molecular sieves” in Tetrahedron Letters 54 (2013) 406-408 report the Passerini coupling of cyclohexyl isocyanide with isatins and carboxylic acids in the presence of 4 Å molecular sieves. This process offers a highly efficient and atom-economic access to 3-acyloxy-3-carboxamido-1,3-dihydro-2H-indol-2-ones in high to excellent yields, but the reaction proceeds only in the presence of a solvent. Moreover, this reaction is limited only to cyclohexyl isocyanide, and the scope of the reaction is not broad. An article titled “Fast and efficient solvent-free Passerini reaction” by Till Bousquet et a. in Tetrahedron Letters 01/2012; 53(3):306-308 reports Passerini three component condensation between a carboxylic acid, an aldehyde, and an isocyanide at high temperature under solvent-free conditions was developed. This methodology allows the formation of a broad range of α-acyloxyamides in excellent yields in short reaction times, but suffers from drawbacks including being restricted to aldehydes and being conducted at higher temperatures.
Hence, an easier, efficient and environment friendly process for the synthesis of oxindole derivatives is highly desired to overcome the above mentioned problems. Further, it would be desirable to improve yields over prior art processes and also to conduct the process at milder conditions including low temperatures.